Activation of Downstream mTORC1 Target Ribosomal Protein S6 Kinase (S6K) Can Be Found in a Subgroup of Dutch Patients with Granulomatous Pulmonary Disease.

Raisa Kraaijvanger,Jan C Grutters,Kees Seldenrijk,Thomas Weichhart,Marcel Veltkamp,Jayne Louise Wilson,Jan Damen,Els Beijer

doi:10.3390/cells10123545

Raisa Kraaijvanger, Jan C Grutters + Show 6 more

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https://doi.org/10.3390/cells10123545

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Abstract

Mechanistic target of rapamycin complex 1 (mTORC1) has been linked to different diseases. The mTORC1 signaling pathway is suggested to play a role in the granuloma formation of sarcoidosis. Recent studies demonstrated conflicting data on mTORC1 activation in patients with sarcoidosis by measuring activation of its downstream target S6 kinase (S6K) with either 33% or 100% of patients. Therefore, the aim of our study was to reevaluate the percentage of S6K activation in sarcoidosis patients in a Dutch cohort. To investigate whether this activation is specific for sarcoid granulomas, we also included Dutch patients with other granulomatous diseases of the lung. The activation of the S6K signaling pathway was evaluated by immunohistochemical staining of its downstream effector phospho-S6 in tissue sections. Active S6K signaling was detected in 32 (43%) of the sarcoidosis patients. Twelve (31%) of the patients with another granulomatous disorder also showed activated S6K signaling, demonstrating that the mTORC1 pathway may be activated in a range for different granulomatous diseases (p = 0.628). Activation of S6K can only be found in a subgroup of patients with sarcoidosis, as well as in patients with other granulomatous pulmonary diseases, such as hypersensitivity pneumonitis or vasculitis. No association between different clinical phenotypes and S6K activation can be found in sarcoidosis.

Highlights

The mechanistic target of rapamycin is a serine–threonine protein kinase and the main component of both Mechanistic target of rapamycin complex 1 (mTORC1) and mTORC2 complexes, which regulate different processes, such as cell growth, proliferation, autophagy, and angiogenesis [1,2]. mTORC1 regulates activation of innate immune cells, such as monocytes, macrophages, as well as dendritic cells
Previous studies already suggested a possible role for the cellular signaling pathway mTORC1 in the granuloma formation of sarcoidosis. The results from these studies conflicted each other, compelling us to address the question in which percentage of sarcoidosis patients mTORC1 might play a role in granuloma formation and/or maintenance
Our data reveal that in approximately 43% of Dutch patients with sarcoidosis, activation of the mTORC1 pathway measured by the downstream kinase S6 kinase (S6K) can be detected inside granulomas

Summary

Introduction

The mechanistic target of rapamycin (mTOR) is a serine–threonine protein kinase and the main component of both mTORC1 and mTORC2 complexes, which regulate different processes, such as cell growth, proliferation, autophagy, and angiogenesis [1,2]. mTORC1 regulates activation of innate immune cells, such as monocytes, macrophages, as well as dendritic cells. Two important downstream components of the mTORC1 pathway are the target protein S6 kinase (S6K), which increases the overall translation capacity of cells when activated, and eukaryotic initiation factor 4E-binding protein (4EBP1), which is crucial for ribosome recruitment [1,2,3,4]. Dysregulation of this fundamental signaling pathway has already been linked to different diseases, such as metabolic disorders, tuberous sclerosis complex, and multiple types of cancer [1]. In gastric cancer and non-small lung cancer, activation of mTOR pathway was found in 54% and 71% of patients, respectively [7,8], and in the latter associates with a poor prognosis [8]

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